Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-13
2002-08-20
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S401000
Reexamination Certificate
active
06436987
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel polymorphic crystalline forms of anhydrous (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid, and to methods for the preparation thereof. (3S-trans)-2-[3,4-dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)-benzoic acid, hereinafter compound(I), is a benzopyran-derived antagonist of leukotriene B
4
(hereinafter, “LTB
4
”), and is therefore useful in the treatment of numerous diseases including inflammatory diseases. Compound (I) has the chemical formula C
24
H
17
O
4
F
3
, is also appropriately named as [(+)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid], and has the following stereospecific structure.
The invention also relates to a novel crystalline salt and a novel crystalline hydrate of compound (I). The novel crystalline forms of the invention possess one or more characteristics selected from enhanced thermal stability, improved solubility in aqueous solvents, improved bioavailability, ready isolation from water-wet solvents, and capacity to be formulated as a pharmaceutical composition using wet granulation techniques, that surprisingly facilitate the use of compound (I) in medical applications.
REPORTED DEVELOPMENTS
Leukotrienes are a class of compounds derived from the 20-carbon fatty acid skeleton of arachidonic acid which function as locally acting hormone-like chemical mediators. Leukotrienes define one major division of the eicosanoids, a large family of chemical mediators, derived from 20 carbon-polyunstaturated fatty acids, and which also includes the lipoxins, thromboxanes, hydroperoxy fatty acids, and prostaglandins.
In general, synthesis of eicosanoids is stimulated by local tissue damage, hormonal stimuli, or via cellular activation pathways (such as binding of IgE immunoglobins to cell surface receptors). Unlike stored, pre-formed chemical mediators, eicosanoid lipid mediators typically appear in cells only after activation events. Eicosanoids, in turn, bind to specific cell surface receptors thereby mediating a wide variety of effects in numerous tissues. Antagonist compounds have been developed for various classes of eicosanoids that act to prevent the normal effects of eicosanoid-receptor binding.
In one recognized pathway, arachidonic acid is produced in activated cells from cell membrane phospholipids by the action of one or more lipase enzymes. Arachindonic acid is first transformed into an unstable epoxide, known as leukotriene A4 (LTA
4
) which can be enzymatically hydrated (via 5-lipoxygenase) to leuokotriene B4 (LTB
4
). Alternatively, via the action of the enzyme glutathione S-transferase, LTA
4
may be covalently coupled to glutathione to form leuoktriene C4 (LTC
4
), from which leuoktriene D4 (LTD
4
), and leuoktriene E4 (LTE
4
), may be subsequently formed by elimination of &ggr;-glutamyl and then glycinyl residues, respectively.
The cysteinyl leukotrienes (C
4
, D
4
and E
4
) are likely the principal mediators of acute attacks of IgE-mediated bronchial asthma, and are more that 100-fold more potent than histamine, on a molar basis, at effecting bronchiole constriction. Accordingly, there is considerable interest in developing pharmaceuticals that interfere with leukotriene-mediated processes by acting as antagonists of leukotriene-receptor interactions.
The biological role of leukotriene B4 was first appreciated in the 1980s when addition of LTB
4
to isolated neutrophils (a type of white blood cell) induced chemotactic, chemokinetic and aggregation responses, and increased adhesion of neutrophils to endothelial cell monolayers. Because of their capacity to engulf and destroy bacteria, for example, neutrophils play a key role in responding to sites of infection in the body. Neutrophils were also originally identified as a major source of LTB
4
. Subsequently it has been determined that other types of cells that participate in immune and inflammation-related pathways (i.e. monocytes, macrophages, keratinocytes, lymphocytes and mast cells) also produce LTB
4
under circumstances likely associated with pathophysiologic stimulation. LTB
4
has also been shown to participate in gene transcription and translation for various cytokines and their receptors in various T and B cells of the immune system. Taken together, these and other results indicate that LTB
4
plays a broad role in inflammatory processes. That neutrophils both secrete and chemotactically respond to LTB
4
strongly suggests a feedback mechanism to regulate the inflammatory response.
Generally speaking, the inflammatory response is a protective mechanism that facilitates response to local injury. For example, leakage of tissue fluids into the affected area facilitates contact with antibodies, and also permits the migration of white blood cells to directly combat any injurious agent. Unfortunately, an inflammatory response may be inappropriate, that is, it may continue for an excessive period of time or involve participation by inflammatory system components that, unfortunately, act to damage to the body, thereby contributing to, or even defining, a disease state. Accordingly, there are numerous circumstances where it is medically appropriate to interefere with inflammatory processes.
Since inflammatory pathways are involved in the pathology of numerous disease states, compounds that act as antagonists to leukotriene B4-mediated effects define a class of important pharmaceutical agents. The involvement of LTB
4
in a variety of human inflammatory diseases, and other diseases, is also suggested by the effectiveness of potent LTB
4
receptor antagonists in preclinical animal disease models (for a review, see H. J. Showell, et al.,
Journal of Pharmacology and Experimental Therapeutics,
285 (3), pp. 946-954, 1998, and original citations therein).
Pharmaceutical agents that inhibit the action of LTB
4
are useful in the treatment of diseases induced by LTB4, or to which LTB
4
contributes, including, without limitation, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease; disorders of the skin including psoriasis, eczema, erythema, pruritis, and acne; stroke, and any disease marked by reperfusion injury; graft rejection; autoimmune diseases; allergy and asthma; and, for example, any other condition where marked neutrophil infiltration occurs. It will be recognized that more than one such state may occur simultaneously, or that an individual disease state may have more than one cause, nonetheless being treatable according to the practice of the present invention.
LTB
4
antagonists are also disclosed in European patent publications 276 064 and 292 977 which refer respectively to (a) diphenyl ethers, benzophenones, and other compounds containing two phenyl groups, and (b) derivatives of 7-(3-alkoxy-4-alkanoyl-phenoxy)alkoxybenzopyran. Additional classes of LTB
4
antagonists, and original citations thereto, are mentioned in H. J. Showell et al., “Inhibitors and Antagonists of Cyclooxygenase, 5-Lipoxygenase, and Platelet Activating Factor”, in Inflammation: Basic Principals and Clinical Correlates, 3rd ed., J. I. Gallin et al., chapter 74, pp. 1177-1193, Lippincott, Philadelphia, Pa., 1999.
The compound of the present invention is disclosed generally in U.S. Pat. No. 5,552,435 which is incorporated by reference herein as if fully set forth.
It has now been discovered that anhydrous compound (I) can exist in crystalline, polymorphic forms, which differ from each other in their stability, physical properties, spectral data, and methods of preparation. It has also been discovered that particular salts and hydrates of compound (I) have properties that contribute to their usefulness as pharmaceuticals.
As aforementioned, each novel polymorphic crystalline form of compound (I) or salt or hydrate of compound (I), as herein described, possesses one or more characteristics (selected from enhanced thermal stability, improved solubility in aqueous solv
Allen Douglas J. M.
Joseph David B.
Sage Nancy A.
Dentz Bernard
Donahue Victor
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